Leishmaniasis pentamidine

Pentamidine has been used for the prophylaxis and treatment of African trypanosomiasis. It also has some value for treating visceral leishmaniasis. Pentamidine rapidly disappears from the pla.sma after intravenous injection and is distributed to the tissues, where it is stored for a long period. This property probably contributes to the usefulness of the drug as a prophylactic agent. 

The answer is d. (Hardman, p 989.) Both trimethoprim-sulfamethoxazole and pentamidine are effective in pneumonia caused by E carinii. This protozoal disease usually occurs in immunodeficient patients, such as those with AIDS. Nifurtimox is effective in trypanosomiasis and metronidazole in amebiasis and leishmaniasis, as well as in anaerobic bacterial infections. Penicillins are not considered drugs of choice for this particular disease state. 

Drugs used for trypanosomiasis include nifurtimox, suramin, melarsoprol and pentamidine. The first choice agent for treating leishmaniasis is sodium stibogluconate. Alternatives are amphotericin B (see Section V.a) and pentamidine. 

Pentamidine is active against Pneumocystis carinii, trypanosomes, and leishmaniasis unresponsive to pentavalent antimonials. It is an alternative agent for the treatment of P. carinii pneumonia. Although it is more toxic than trimethoprim-sulfamethoxazole, it has been widely used in patients with acquired immunodeficiency syndrome (AIDS), in whom P. carinii infection is common. 

Pentamidine is an alternative drug for visceral leishmaniasis, especially when sodium stibogluconate has failed or is contraindicated. Pentamidine is also a reserve agent for the treatment of trypanosomiasis before the CNS is invaded. This characteristic largely restricts its use to Gambian trypanosomiasis. 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

It is used in the treatment of pneumocystosis (pulmonary and extrapulmonary disease caused by P. carinii), African trypanosomiasis (disease caused by Trypanosoma brucei) and leishmaniasis. Systemic pentamidine is highly toxic and can lead to severe hypotension, tachycardia, dyspnea, dizziness, hypoglycemia. Other adverse effects are skin rash, metallic taste, gastrointestinal symptoms, thrombocytopenia and cardiac arrhythmias. 

Pentamidine is an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis, with similar efficacy, although resistance has been reported. The drug has been successful in some cases that have failed therapy with antimonials. The dosage is 2-4 mg/kg intramuscularly daily or every other day for up to 15 doses, and a second course may be necessary. Pentamidine has also shown success against cutaneous leishmaniasis, but it is not routinely used for this purpose. 

Leishmaniasis Skin mucocutaneous tissues viscera Amphotericin B Itraconazole, ketoconazole pentamidine, sodium stibogluconate... 

Leishmaniasis, visceral (L donovani, L chagasi, L infantum) or mucosal (L braziliensis) Sodium stibogluconate,4 20 mg/kg/d IV or IM for 28 days Meglumine antimonate2 or- Pentamidine or- Amphotericin B or- Miltefosine2... 

Curcumin possesses leishmanicidal effects in vitro and is more potent than the standard leishmaniasis drug, pentamidine. LD50 for leishmanicidal activity in vitro is found to be 37.6 3.5pM (Koide et al., 2002). 

Pentamidine, an aromatic diamine, has been known since the late 1930s as a treatment for trypanosomiasis and some forms of leishmaniasis. In recent times it has been extensively used in the treatment of Pneumocystis jiroveci pneumonia. Its mechanism of action is probably related to inhibition of dihydrofolate reductase and inhibition of oxidative phosphorylation and nucleic acid synthesis, as well as an effect on aerobic glycolysis. 

In an uncontrolled study in French Guiana, intramuscular pentamidine isethionate (two 4 mg/kg injections 48 hours apart) in 198 patients with cutaneous leishmaniasis produced a cure rate of 87% 80% of treatment failures responded to an identical second course (1). Compared with published studies, adverse events were relatively mild pain on injection (54%), gastrointestinal effects (53%), and hypotension (8%). There were no dysrhythmias or glucose abnormalities. This may reflect the brief course of pentamidine used. 

Pentamidine is the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Pentamidine mesylate in 235 patients and pentamidine isethionate in 80 patients have been compared in a retrospective study the cure rate (healing without relapse) was nearly 90% in both groups (2). Relapses occurred in about 10% of patients in both groups. Minor adverse effects, such as pain at the injection site, bitter taste, and nausea, occurred with both drugs in about 65% of patients. Respiratory tract problems occurred in under 10% of patients who took pentamidine isethionate but were uncommon in those who took pentamidine mesylate. 

Two patients (aged 31 and 38 years) with cutaneous leishmaniasis given intramuscular pentamidine 600 mg twice in 48 hours developed rhabdomyolysis (12). They recovered with fluid replacement and alkaline diuresis. 

Lieber-Mbomeyo A, Lipsker D, Milea M, Heid E. Rhabdomyolyse induite par I isethionate de pentamidine (Pentacarinat) lors du traitement d une leishmaniose cutanee. 2 cas. [Rhabdomyolysis induced by pentamidine (Pentacarinat) during treatment of cutaneous leishmaniasis 2 cases.] Ann Dermatol Venereol 2002 129(1 Pt l) 50-2. 

Nacher M, Carme B, Sainte Marie D, Couppie P, Clyti E, Guibert P, Pradinaud R. Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol 2001 95(4) 331-6. 

Pentamidine is a diamidine compound developed more than five decades ago [128]. Initially, it was only used for its antiprotozoal properties against African trypanosomiasis [129], and visceral leishmaniasis [130]. Subsequently, its use was extended to the treatment and prophylaxis of PCP in immunosuppressed patients [131-133]. The use of pentamidine, which was rare in countries without tropical diseases, increased notably because of the high incidence of PCP observed in patients with AIDS [72, 97, 134-136]. Until 1984, pentamidine distribution in the USA was restricted indeed it was only available through the Center for Disease Control. Although TMP-SMZ is regarded as the preferred treatment for PCP [102, 103], pentamidine or less frequently used combinations (trime-trexate/leucovorin, clindamycin/ primaquine [137]) are reasonable alternatives when TMP-SMZ is not tolerated or is without effect [138]. 

Antoniskis et al reported four cases of reversible acute kidney injury in patient with AIDS who received both intravenous pentamidine (for PCP) and amphotericin B (for systemic mycoses). Of note, nephrotoxicity did not develop in three AIDS patients treated with both TMP-SMZ and amphotericin B or in two patients who concomitantly received inhaled pentamidine and amphotericin B [160]. Reports of renal damage in patients receiving parenteral pentamidine for the treatment of non-HIV diseases continue. Reversible acute kidney injury and nephrotic syndrome were documented in a young child given pentamidine mesylate and an antimonial salt for the treatment of visceral leishmaniasis [161]. In Africa (Kenya) patients with visceral leishmaniasis have developed renal toxicity during prolonged treatment (1 to 10 months) with pentamidine [162]. 

Leishmaniasis Leishmania donovani, L tropica, L. mexicana, L. brasiliensis Pentostam, glucantime, urea stibamine, pentamidine, WR-6026, al-lopurinol, allopurinol riboside, amphotericin B... 

Table 7-2 lists the various drugs that have been useful for a variety of protozoal diseases. It will be noted that several are indicated for more than one condition (e.g., pentamidine against leishmaniasis, trypanosomiasis, and pneumocystosis). Several of these not yet discussed will now be considered. 

Pentamidine (4 mg/kg once a day for 14 days) is indicated in the treatment of Pneumocystis carinii pneumonia (PCP), prevention of PCP in high-risk, HIV-infected patients, and in the treatment of trypanosomiasis and visceral leishmaniasis. 

Pentamidine is an alternative agent for the treatment of antimony-resistant visceral leishmaniasis, although the availability of newer, less toxic agents (e.g., liposomal preparations of amphotericin and miltefosine) may decrease its use. Pentamidine is also used as an alternative agent in the treatment and prophylaxis of pneumocystis pneumonia caused by the ascomycetous fungus Pneumocystis jiroveci (formerly known as Pneumocystis carinii). T. brucei rhodesiense is refractory to treatment by pentamidine for... 

Pentamidine has been used successfully in comses of 12 to 15 IM doses of 2 to 4 mg/kg either daily or every other day to treat visceral leishmaniasis (kala-azar caused by L. donovani). This compound provides an alternative to antimonials or lipid formulations of amphotericin B for patients who cannot tolerate the latter agents. Pentamidine isethionate given as fom IM doses of 3 mg/kg every other day has enjoyed some success in the treatment of cutaneous leishmaniasis (Oriental sore caused by L. tropica) but is not used routinely to treat this infection. 

---